Department of Thoracic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee.
Cancer Epidemiol Biomarkers Prev. 2019 Apr;28(4):715-723. doi: 10.1158/1055-9965.EPI-18-0935. Epub 2019 Mar 20.
Identifying genetic variants with pleiotropic associations across multiple cancers can reveal shared biologic pathways. Prior pleiotropic studies have primarily focused on European-descent individuals. Yet population-specific genetic variation can occur, and potential pleiotropic associations among diverse racial/ethnic populations could be missed. We examined cross-cancer pleiotropic associations with lung cancer risk in African Americans.
We conducted a pleiotropic analysis among 1,410 African American lung cancer cases and 2,843 controls. We examined 36,958 variants previously associated (or in linkage disequilibrium) with cancer in prior genome-wide association studies. Logistic regression analyses were conducted, adjusting for age, sex, global ancestry, study site, and smoking status.
We identified three novel genomic regions significantly associated (FDR-corrected <0.10) with lung cancer risk (rs336958 on 5q14.3, rs7186207 on 16q22.2, and rs11658063 on 17q12). On chromosome16q22.2, rs7186207 was significantly associated with reduced risk [OR = 0.43; 95% confidence interval (CI), 0.73-0.89], and functional annotation using GTEx showed rs7186207 modifies gene expression. The minor allele at rs336958 on 5q14.3 was associated with increased lung cancer risk (OR = 1.47; 95% CI, 1.22-1.78), whereas the minor allele at rs11658063 on 17q12 was associated with reduced risk (OR = 0.80; 95% CI, 0.72-0.90).
We identified novel associations on chromosomes 5q14.3, 16q22.2, and 17q12, which contain , and genes, respectively. SNPs within these regions have been previously associated with multiple cancers. This is the first study to examine cross-cancer pleiotropic associations for lung cancer in African Americans.
Our findings demonstrate novel cross-cancer pleiotropic associations with lung cancer risk in African Americans.
鉴定具有跨多种癌症的多效关联的遗传变异可以揭示共同的生物学途径。先前的多效性研究主要集中在欧洲裔个体上。然而，可能会出现特定于人群的遗传变异，并且不同种族/民族群体之间的潜在多效关联可能会被忽略。我们研究了非裔美国人的肺癌风险与跨癌症的多效关联。
我们在 1410 例非裔美国肺癌病例和 2843 例对照中进行了多效性分析。我们检查了先前在全基因组关联研究中与癌症相关（或处于连锁不平衡状态）的 36958 个变体。进行了逻辑回归分析，调整了年龄、性别、全球祖先、研究地点和吸烟状况。
我们鉴定出三个与肺癌风险显著相关的新基因组区域（经 FDR 校正后<0.10）（5q14.3 上的 rs336958、16q22.2 上的 rs7186207 和 17q12 上的 rs11658063）。在 16q22.2 上，rs7186207 与降低的风险显著相关[OR=0.43；95%置信区间（CI），0.73-0.89]，并且使用 GTEx 进行的功能注释表明 rs7186207 改变了 基因的表达。5q14.3 上 rs336958 的次要等位基因与肺癌风险增加相关（OR=1.47；95%CI，1.22-1.78），而 17q12 上 rs11658063 的次要等位基因与风险降低相关（OR=0.80；95%CI，0.72-0.90）。
我们在包含 、 和 基因的 5q14.3、16q22.2 和 17q12 染色体上鉴定到了新的关联。这些区域内的 SNP 先前与多种癌症相关。这是第一项研究非裔美国人肺癌的跨癌症多效性关联。
我们的发现表明，非裔美国人的肺癌风险与跨癌症的多效关联具有新颖性。
